Sometimes two things seem to be indistinguishable, even though they really are quite different.

As I discussed last week, biochemists have recently come to recognize that biochemical synonyms—synonymous codons that specify the same amino acid in the genetic code—are actually distinct even though they have long been regarded as indistinguishable. It turns out that some codons are better suited than others for producing functional proteins. Biochemists refer to these preferred biochemical synonyms as optimal codons.

A new study demonstrates that the usage of optimal codons appears to be optimized as well, providing added evidence that life stems from the work of a Creator. Last week I presented the background information necessary to appreciate this new insight. This week I describe the research and discuss its implications.

Genetic Code

As I discussed last week, the genetic code constitutes a set of rules that translate the information stored in the nucleotide sequences of DNA into the amino acid sequences of proteins. Nucleotide triplets called codons represent the fundamental units of the genetic code.

Sixty-four codons make up the genetic code. Because the genetic code only needs to encode twenty amino acids, some of the codons are redundant. That is, different codons signify the same amino acid. In fact, up to six different codons specify some amino acids. Other amino acids are represented by only one codon.

Synonymous and Nonsynonymous Mutations

A mutation refers to any change that takes place in the DNA nucleotide sequence. Substitution mutations are one common type. When a substitution mutation occurs, one (or more) of the nucleotides in the DNA strand is replaced by another nucleotide. Sometimes substitution mutations generate a new codon that specifies the same amino acid as initially encoded. Biochemists refer to this type of change as a synonymous mutation. When a mutation produces a codon that specifies a different amino acid, it’s called a nonsynonymous mutation.

Nonsynonymous mutations can be deleterious if they affect a critical amino acid or if they significantly alter the chemical and physical profile along the protein chain. If the substituted amino acid possesses dramatically different physicochemical properties from the native amino acid, the protein folds improperly. This improper folding impacts the protein, yielding a biomolecule with reduced or even lost function.

Biochemists used to think that synonymous mutations had no impact whatsoever on protein structure, and hence function, since the amino acid sequence specified by the synonymous change would be identical.

Recently, biochemists have recognized that their views about synonymous changes were wrong. Even though the amino acid sequence doesn’t change, the protein structure can be altered. This altered structure stems from differences in the folding of the protein chain due to differences in the rate of protein production. Synonymous codons are read at differing rates. And the folding pattern will change depending upon the speed of protein construction.

Additionally, some synonymous codons are more likely to be misread by the cell’s machinery than others. So even though the information needed to make a particular protein isn’t changed, the wrong amino acid still may be introduced into the protein chain because of the codon used. This error, of course, can lead to structural and functional abnormalities in that protein, just as if a nonsynonymous change had occurred.

In either case, misfolded proteins can result. And this misfolding has disastrous consequences for the cell.

Misfolded Proteins

Misfolded proteins can cause profound problems for the cell. Their negative consequences extend beyond loss of function for the misfolded protein. Improperly folded proteins have a global impact on cellular health. These deformed proteins tend to form aggregates inside the cell, fouling up its inner workings. Biochemists think that many neurodegenerative diseases may have an etiology that involves aggregates formed from misfolded proteins. Misfolded proteins can also spread the misery to properly folded proteins. Once a protein has adopted a nonnative structure it can induce structurally-intact proteins to become improperly folded, enticing them to join the aggregated mess inside the cell. (As the biblical saying goes, “A little leaven, leavens the whole lump of dough.”)

In fact, even one improperly folded protein is enough to destabilize the ensemble of proteins inside a cell. (Go here for a technical article about the effect of misfolded proteins on global protein stability.) If all these problems weren’t enough, misfolded proteins can even disrupt cell membranes.

Optimal Codons are Optimally Distributed in Gene Sequences

Motivated by the impact of synonymous codons on protein folding, a team of biochemists conducted a study designed to explore the usage of optimal codons within genes and their relationship to protein folding. This research looked for correlations between codon usage and a number of parameters in a massive database of DNA sequences from a wide range of representative organisms, including the bacterium, E. coli; the yeast, S. cerevisiae; the nematode, C. elegans; the fruit fly, D. melangaster; the mouse, M. musculus; and humans.

The researchers discovered that critical amino acids tend to be specified by optimal codons. This makes sense, because errors in these positions will be much more detrimental than other positions in the protein chain. Mistakes in these positions are also much more likely to alter protein folding.

They also determined that proteins produced at relatively high levels in the cell have a greater fraction of optimal codons than proteins that occur at low levels. Again, this reflects an elegant strategy. The more often a protein is produced the more opportunity exists for protein misfolding to happen.

The biochemists also identified tissue dependence for the distribution of optimal codons. Tissues comprised of cells that are long-lived with a low turnover rate (like neurons) have proteins encoded by genes with a high fraction of optimal codons compared to rapidly replaced cell types. This again displays a remarkable biological logic. These types of cells would be susceptible to the accumulation of protein aggregates built up over the course of an organism’s life time. The increase of protein aggregates would not be much of an issue for short-lived cells with a high turnover rate.

One final note: The workers found these correlations in the data for all six organisms, suggesting that they have uncovered a universal pattern among all life-forms.

The bottom line: It looks as if the usage of optimal codons is optimized and appears to be undergirded by an impeccable biochemical rationale.

The Implications

Systems and objects produced by human designers are optimized. Optimization in an engineered system requires extensive planning and forethought and, therefore, stands as a hallmark of intelligent design. In fact, optimization is often synonymous with superior design.

As I describe in The Cell’s Design, life scientists have discovered that, like human designs, many biochemical systems are optimized according to a purpose. The usage of optimal codons marks just one more example.

The optimality of biochemical systems far exceeds the accomplishments of the finest human engineers and designers, in a way befitting a supernatural Creator. Biochemical optimization indicates that life must have materialized from the Divine Artist’s hand.

Dr. Fazale Rana

In 1999, I left my position in R&D at a Fortune 500 company to join Reasons to Believe because I felt the most important thing I could do as a scientist is to communicate to skeptics and believers alike the powerful scientific evidence—evidence that is being uncovered day after day—for God’s existence and the reliability of Scripture. Read more about Dr. Fazale Rana

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